1. Abstract For many years, APOE has been the only major gene known to increase disease risk for Alzheimer disease (AD). However, genome wide association studies (GWAS) have identified over 25 loci as risk or protective factors for AD. Several of the genetic variations identified by GWAS, including changes in TREM2, are of major interest for the AD research community. The genetic information related to the brains harvested at Alzheimer Disease Centers (ADC) is of vital importance. It is necessary to expand our knowledge related to the genetics of these well characterized brains. The goal of the requested supplement for the IADC-NPC is analyzing genetically, by next- generation sequencing (NGS), a cohort of autopsy-confirmed AD cases that have been already neuropathologically characterized at the IADC. NGS is also known as high-throughput sequencing and includes whole exome sequencing (WES) and whole genome sequencing (WGS). Further neuropathologic examinations will also be performed to further analyze brain tissue?s inflammatory reaction, vulnerability of anatomical regions, and potential co-morbidities. This supplement application aims at the genetic characterization of brains from neuropathologically confirmed AD cases, currently available at the IADC. In addition to adding a new well-characterized cohort for genetic analyses, the results obtained from the proposed studies will allow us to utilize the available tissue (fixed and frozen) in more advanced studies, using novel technologies, such as confocal microscopy, mass spectrometry, and cryo-electron microscopy. Our main hypothesis is that the genetic analysis of well-characterized brain tissue may lead to the discovery of novel risk or protective genes (or variants) for AD. By deepening the knowledge of the biology of structural and genetic properties associated to pathologic CNS tissue, the brains we study will become an invaluable resource for the AD research community at-large. To accomplish our goals, we propose to isolate genomic DNA from over 350 cases stored at the NPC with a primary diagnosis of AD for NGS analysis, and to determine the presence of additional pathologies co-occurring with AD. Finally, we will associate genetic information with brain tissue (fixed and frozen) to be able to be distributed to researchers.